The present invention relates to a superoxide radical inhibitor containing an azole derivative as the effective ingredient.
1. Background Art
It is thought that neutrophilic leukocytes show a germicidal activity to foreign invaders in living bodies by a wondering reaction, a feeding action, generation of superoxide radical (O2xe2x88x92) and release of lysosomal enzyme and play an important role in protection of living body. While neutrophilic leukocytes have the above reaction for living body protection, it has been made clear that the superoxide radical released by tissues or neutrophilic leukocytes during ischemia of tissues and subsequent blood re-perfusion or during acute inflammation at early stage destroys cells, causing functional disturbances of tissues [B. R. Lucchesi: Annual Review of Pharmacology and Toxicology, Vol. 26, p. 201 (1986); B. A. Freeman et al.: Laboratory Investigation, Vol. 47, p. 412 (1982); E. Braunwald, R. A. Kloner: Journal of Clinical Investigation, Vol. 76, p. 1713 (1985); J. L. Romson et al.: Circulation, Vol. 67, p. 1016 (1983)].
2. Disclosure of the Invention
Based on the thought that the major cause for the above-mentioned disturbances in cells, in particular the disturbances after ischemia and re-perfusion in heart, brain, kidney, lung and digestive tract lies in the superoxide radical released by neutrophilic leukocytes, the present invention has an object of providing a new drug for inhibiting the release of the superoxide radical.
The present inventors made study for the above object and, as a result, found that certain azole derivatives show a very strong inhibitory activity for release of superoxide radical in living bodies. Further study based on the finding has led to the completion of the present invention.
Therefore, the present invention relates to a superoxide radical inhibitor containing, as the effective ingredient, at least one of the azole derivatives represented by the following general formula (1).
Azole derivatives represented by the general formula (1), 
{wherein R1 and R3 which may be the same or different, each represent a phenyl group which may have 1 to 5 substituents on the phenyl ring, selected from the group consisting of an alkoxy group, a tri-lower alkyl group-substituted silyloxy group, a lower alkyl group, a hydroxyl group, a lower alkenyloxy group, a lower alkylthio group, a phenyl group which may have a group selected from the group consisting of a thiazolyl group having, as a substituent on the thiazolyl ring, a phenyl group which may have a lower alkoxy group on the phenyl ring, a carboxyl group and a hydroxyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a halogen atom, a nitro group, a group of the formula, 
{wherein A represents a lower alkylene group or a group of the formula 
l represents 0 or 1; R8 and R9, which may be the same or different, each represent a hydrogen atom, a lower alkyl group, a lower alkanoyl group, an amino-lower alkyl group which may have a lower alkyl group as a substituent, or a piperidinyl-lower alkyl group, further R8 and R9 as well as the adjacent nitrogen atom being bonded thereto, together with or without other nitrogen atom or oxygen atom may form a five- to six-membered saturated or unsaturated heterocyclic group; said five- to six-membered heterocyclic group may have a lower alkanoyl group or a lower alkyl group as a substituent.], a lower alkanoyl group, a lower alkanoyloxy group, an alkoxycarbonyl group, a cyano group, a tetrahydropyranyloxy group which may have 1-4 substituents selected from the group consisting of a hydroxyl group, a lower alkoxycarbonyl group, a phenyl-lower alkoxy group, a hydroxyl group- or lower alkanoyloxy group-substituted lower alkyl group and a lower alkanoyloxy group, an amidino group, a hydroxysulfonyloxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a mercapto group, a lower alkoxy-substituted lower alkoxy group, a lower alkyl group having hydroxyl groups, a lower alkenyl group, an aminothiocarbonyloxy group which may have a lower alkyl group as a substituent, an aminocarbonylthio group which may have a lower alkyl group as a substituent, a lower alkanoyl-substituted lower alkyl group, a carboxy group, a group of the formula, 
(R21 and R22 which may be the same or different, each represent a hydrogen atom or a lower alkyl group.), a phenyl-lower alkoxycarbonyl group, a cycloalkyl group, a lower alkynyl group, a lower alkoxycarbonyl-substituted lower alkyl group, a carboxy-substituted lower alkyl group, a lower alkoxycarbonyl-substituted lower alkenyl group, a carboxy-substituted lower alkenyl group, a lower alkylsulfonyloxy group which may have a halogen atom, a lower alkoxy-substituted lower alkoxycarbonyl group, a lower alkenyl group having halogen atoms and a phenyl-lower alkoxy group; a phenyl group having a lower alkylenedioxy group; a 5- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic residual group having 1 to 2 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom [said heterocyclic residual group may have 1 to 3 substituents selected from the group consisting of an oxo group, an alkyl group, a benzoyl group, a lower alkanoyl group, a hydroxyl group, a carboxy group, a lower alkoxycarbonyl group, a lower alkylthio group, a group of the formula, 
(A is the same as defined above, R23 and R24, which may be the same or different, each represent a hydrogen atom or a lower alkyl group; further, R23 and R24 as well as the adjacent nitrogen atom being bonded thereto, together with or without other nitrogen atom or oxygen atom may form a five- to six-membered saturated heterocyclic group; said five- to six-membered heterocyclic group may have a lower alkyl group as a substituent.), a cyano group, a lower alkyl group having hydroxyl groups, a phenylaminothiocarbonyl group and an amino-lower alkoxycarbonyl group which may have a lower alkyl group as a substituent.]; a lower alkyl group; a lower alkoxycarbonyl-lower alkyl group; a lower alkoxycarbonyl group; a carbamoyl-lower alkyl group; a 2,3-dihydroindenyl group which may have an oxo group or/and a hydroxyl group as substituent(s); a phenyl-lower alkyl group which may have a lower alkoxy group as a substituent on the phenyl ring or may have a hydroxyl group as a substituent on the lower alkyl group; a benzoyl group which may have a lower alkoxy group as a substituent on the phenyl ring; a phenyl-lower alkenyl group which may have a lower alkoxy group as a substituent on the phenyl ring; a piperazinyl-lower alkyl group which may have a lower alkyl group on the piperazine ring; or an adamantyl group; R3 may represent, besides the above, a hydrogen atom; R2 represents a hydrogen atom, a phenyl group, a halogen atom, a lower alkoxycarbonyl group, a lower alkyl group, an amino-lower alkyl group (which may have a lower alkyl group as a substituent), or a dihydrocarbostyril group; R2 and R3 may bond to each other to form a group of the formula, 
a group of the formula, 
or a group of the formula, 
X represents a sulfur atom or an oxygen atom.}, and salts thereof.
The compounds of the present invention have an activity of inhibiting the release of superoxide radical from neutrophilic leukocytes or of removing the superoxide radical. Accordingly, they have an action of preventing or lowering the in vivo production of peroxidized lipids. Hence, the compounds are useful as an agent for preventing and treating various disturbances and diseases caused by excessive generation of superoxide radical, in vivo accumulation of peroxidized lipids, or defect of protective organizations therefor. More specifically, the drugs of the present invention are useful in a pharmaceutical field as a drug for protecting various tissue cells from disturbances associated with ischemia and blood re-perfusion, for example, a remedy for ulcers of the digestive tract (e.g. stress ulcer), a remedy for ischemic heart disease (e.g. myocardial infarction, arrhythmia), a remedy for cerebrovascular diseases (e.g. cerebral hemorrhage, cerebral infarction, temporal cerebral ischemic attack), and a hepatic and renal function improver for disturbances caused by transplant, microcirculation failure, etc., or as an agent for inhibiting various cell function disturbances believed to be caused by the superoxide radical abnormally generated by factors other than ischemia, for example, a remedy for Bechcet disease, dermatovascular inflammation, ulcerative colitis, malignant rheumatoid, arthritis, arteriosclerosis, diabetes mellitus, etc.
It is described in Japanese Patent Publication No. 15935/1971 that the compounds represented by the following general formula, 
(wherein R1 is a group selected from the group consisting of a hydrogen atom and a straight-chain or branched-chain lower alkyl group of 1 to 5 carbon atoms; R2 is a group selected from the group consisting of a lower alkyl group having 1 to 5 carbon atoms, a phenylalkyl group which may be substituted with a lower alkyl or lower alkoxy group having 1 to 5 carbon atoms, or substituted with one or more halogen atoms, and a phenyl group; and A is a group selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group and a lower alkyl or lower alkoxy group having 1 to 5 carbon atoms.) have properties which are advantageous for fibrinolysis, platelet stickiness, ulcers and immunological treatments and can be used for prevention and treatment of thrombosis, arteriosclerosis, gastric ulcer and hypersecretion.
Among the compounds of the present invention, the thiazole derivatives represented by the following general formula (A), 
[wherein RA represents a hydrogen atom or a hydroxyl group; R1A and R2A each represent a methoxy group or an ethoxy group; R3A represents a hydrogen atom or a lower alkyl group; RA is substituted at the 4- or 6-position in the phenyl ring; R1A and R2A should not be a methoxy group simultaneously] and their salts contain some compounds which are similar to the compounds of the above prior art in chemical structure; however, the compounds of the present invention are not disclosed in said prior art. Further, the compounds of the present invention, as shown in the pharmacological tests given later in Table 16, exhibit very strong inhibitory activities for releasing superoxide radical, even though as compared with the most similar compounds.
Among the compounds of the present invention, preferable are:
thiazole derivatives represented by the general formula (B), 
{wherein R1B represents a phenyl group which may have 1 to 3 lower alkoxy groups as substituent(s) on the phenyl ring; a phenyl group having a lower alkylenedioxy group; a pyridyl group which may have an oxo group; a thienyl group; a carbostyril group; a pyrazyl group; a pyrrolyl group; a quinolyl group which may have an oxo group; or a 3,4-dihydrocarbostyril group; R2B represents a hydrogen atom; R3B represents a group of the formula, 
[R4B represents an alkoxy group; a tri-lower alkyl group-substituted silyloxy group; a lower alkyl group; a hydroxyl group; a lower alkenyloxy group; a lower alkylthio group; a phenyl group which may have a group selected from the group consisting of a thiazolyl group having, as a substituent on the thiazolyl ring, a phenyl group which may have a lower alkoxy group on the phenyl ring, a carboxyl group and a hydroxyl group; a lower alkylsulfinyl group; a lower alkylsulfonyl group; a halogen atom; a nitro group; a group of the formula, 
(wherein A represents a lower alkylene group or a group 
l represents 0 or 1; R8 and R9, are each the same or different, and are each a hydrogen atom, a lower alkyl group, a lower alkanoyl group, an amino-lower alkyl group which may have a lower alkyl group as a substituent, or a piperidinyl-lower alkyl group; further R8 and R9 well as the adjacent nitrogen atom being bonded thereto, together with or without other nitrogen atom or oxygen atom may form a five- to six-membered saturated or unsaturated heterocyclic group; said five- to six-membered heterocyclic group may have a lower akanoyl group or a lower alkyl group as a substituent.); a lower alkanoyl group; a lower alkanoyloxy group; an alkoxycarbonyl group; a cyano group; a tetrahydropyranyloxy group which may have 1-4 substituents selected from the group consisting of a hydroxyl group, a lower alkoxycarbonyl group, a phenyl-lower alkoxy group, a lower alkanoyloxy group-substituted lower alkyl group and a lower alkanoyloxy group; an amidino group; a hydroxysulfonyloxy group; a lower alkoxycarbonyl-substituted lower alkoxy group; a carboxy-substituted lower alkoxy group; a mercapto group; a lower alkoxy-substituted lower alkoxy group; a lower alkyl group having hydroxyl groups; a lower alkenyl group; an aminothiocarbonyloxy group which may have a lower alkyl group as a substituent; an aminocarbonylthio group which may have a lower alkyl group as a substituent; a lower alkanoyl-substituted lower alkyl group; a carboxy group; a group of the formula, 
(R21 and R22 which may be the same or different, each represent a hydrogen atom or a lower alkyl group.); a phenyl-lower alkoxycarbonyl group; a cycloalkyl group; a lower alkynyl group; a lower alkoxycarbonyl-substituted lower alkyl group; a carboxy-substituted lower alkyl group; a lower alkoxycarbonyl-substituted lower alkenyl group; a carboxy-substituted lower alkenyl group; a lower alkylsulfonyloxy group which may have a halogen atom; a lower alkoxy-substituted alkoxycarbonyl group; a lower alkenyl group having halogen atoms; or a phenyl-lower alkoxy group. m represents 0, 1 or 2.]; or, a phenyl group having 1-3 substituents, on the phenyl ring, selected from the group consisting of a lower alkanoyloxy group, a hydroxysulfonyloxy group, a cyano group, an amidino group, a nitro group, a lower alkylthio group, a lower alkylsulfonyl group, a tetrahydropyranyloxy group which may have 1 to 4 substituents selected from the group consisting of a hydroxyl group, a lower alkoxycarbonyl group, a phenyl-lower alkoxy group, a hydroxyl group- or lower alkanoyloxy group-substituted lower alkyl group and a lower alkanoyloxy group, a phenyl group which may have a group selected from the group consisting of a thiazolyl group which may have, as a substituent on the thiazolyl ring, a phenyl group which may have a lower alkoxy group on the phenyl ring, a carboxyl group and a hydroxyl group, a lower alkyl group having hydroxyl groups, and a group of the formula, 
(R21 and R22 are the same as defined above); a phenyl group having a lower alkylenedioxy group; a lower alkyl group; a lower alkoxycarbonyl-lower alkyl group; a lower alkoxycarbonyl group; a carbamoyl-lower alkyl group; a 2,3-dihydroindenyl group which may have an oxo group or/and a hydroxyl group as substituent(s); a phenyl-lower alkyl group which may have a lower alkoxy group as a substituent on the phenyl ring or may have a hydroxyl ring as a substituent on the lower alkyl group; a benzoyl group which may have a lower alkoxy group as a substituent on the phenyl ring; a phenyl-lower alkenyl group which may have a lower alkoxy group as a substituent on the phenyl ring; a piperazinyl-lower alkyl group which may have a lower alkyl group as a substituent on the piperazinyl ring; or an adamantyl group. When R4B represents a lower alkoxycarbonyl group-substituted lower alkyl group or a carboxy-substituted lower alkyl group, then, m represents 2}, and their salts;
thiazole derivatives represented by the general formula (C), 
[wherein R1C represents a phenyl group which may have 1 to 3 lower alkoxy groups as substituent(s) on the phenyl ring; R2C represents a hydrogen atom; R3C represents a group of the formula, 
(wherein R4C represents a hydrogen atom, a lower alkyl group, a phenyl-lower alkyl group or a lower alkoxy-substituted lower alkyl group; R5C represents an amino group, a lower alkoxy group-substituted lower alkyl group, a lower alkyl group, a nitro group, a lower alkenyl group, a lower alkanoyl group, a lower alkenyl group having halogen atoms, a phenyl-lower alkoxy group, a halogen atom or a hydroxyl group-substituted lower alkyl group; n represents 2)], and their salts;
thiazole derivatives represented by the general formula (D), 
[wherein R1D represents a phenyl group which may have 1 to 3 lower alkoxy groups as substituent(s) on the phenyl ring; R2D represents a hydrogen atom; R3D represents a group of the formula, 
(wherein R4D represents a hydrogen atom or a lower alkyl group; R5D represents an amino group, a lower alkoxycarbonyl-lower alkoxy group, a nitro group, a lower alkenyloxy group, a lower alkoxy-substituted lower alkoxy group, a mercapto group, a lower alkanoyloxy group, an aminocarbonylthio group which may have a lower alkyl group as a substituent, an aminothiocarbonyloxy group which may have a lower alkyl group as a substituent, a carboxy-substituted lower alkoxy group or a lower alkylsulfoniumoxy group which may have a halogen atom)], and their salts;
thiazole derivatives represented by the general formula, 
{wherein R1 is the same as defined above; R2E represents a hydrogen atom; R3E represents a 5- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic residual group having 1 to 2 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom [said heterocyclic residual group may have 1 to 3 substituents selected from the group consisting of an oxo group, an alkyl group, a benzoyl group, a lower alkanoyl group, a hydroxyl group, a carboxy group, a lower alkoxycarbonyl group, a lower alkylthio group, a group of the formula, 
(A and l are the same as defined above; R23 and R24, are each the same or different, and are each represents a hydrogen atom or a lower alkyl group; further R23 and R24 as well as the adjacent nitrogen atom being bonded thereto, together with or without other nitrogen atom or oxygen atom may form a five- to six-membered saturated heterocyclic group; said five- to six-membered heterocyclic group may have a lower alkyl group as a substituent), a cyano group, lower alkyl group having hydroxy groups, a phenylamino- thiocarbonyl group and an amino-lower alkoxycarbonyl group which may have a lower alkyl group as a substituent]}, and their salts; and
thiazole derivatives represented by the general formula (F), 
[wherein R1 is the same as defined above; R2F represents a hydrogen atom, R3F represents a group of the formula, 
(wherein A, l and m are the same as defined above; R8F and R9F which may be the same or different, each represent a lower alkanoyl group, an amino-lower alkyl group which may have a lower alkyl group as a substituent, or a piperidinyl-lower alkyl group; further R8F and R9F as well as the adjacent nitrogen atom being bonded thereto, together with or without other nitrogen atom or oxygen atom may form a five- to six-membered saturated or unsaturated heterocyclic group; said five- to six-membered heterocyclic group may have a lower alkanoyl group or a lower alkyl group as a substituent); R4F is the same as the above-mentioned R4B other than a hydroxyl group)], or their salts.